MITOCHONDRIAL DAMAGE - A POSSIBLE MECHANISM OF THE TOPICAL PHASE OF NSAID-INDUCED INJURY TO THE RAT INTESTINE

Background-The ''topical'' effect of non-steroidal anti-inflammatory d rugs (NSAIDs) seems to be an important cause of NSAID induced gastroin testinal damage.Aim-To examine the possible mechanism of the ''topical '' phase of damage in the small intestine. Methods-Electron microscopy and subcellular organelle marker enzyme studies were done in rat smal l intestine after oral administration of indomethacin (doses varied be tween 5 and 30 mg/kg). The effect of conventional and non-acidic NSAID s on rat liver mitochondrial respiration was measured in vitro in a Cl arke-type oxygen electrode. Results-The subcellular organelle marker e nzymes showed mitochondrial and brush border involvement within an hou r of indomethacin administration. Electron microscopy showed dose depe ndent mitochondrial changes following indomethacin administration cons istent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar du cts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled ox idative phosphorylation in vitro at micromolar concentrations and inhi bited respiration at higher concentrations. In vivo studies with nabum etone and aspirin further suggested that uncoupling or inhibition of e lectron transport underlies the ''topical'' phase of NSAID induced dam age. Conclusion-Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important compon ent of the ''topical'' phase or damage induction.